Flavone acetic acid (FAA) appears to cause tumor regression by a novel mechanism which involves vascular collapse and immunomodulation. We previously reported that clinically relevant concentrations of FAA inhibited endothelial cell proliferation and capillary tube formation in vitro, but did not impair cell function or compromise viability. We now report that the response of cultured monkey aortic endothelial cells (MAEC) to FAA was not altered by the presence of interferon alpha, interferon gamma, or interleukin-2. The presence of tumor cells sensitive to FAA in vivo did not sensitize the endothelial cells to FAA. FAA inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). FAA (250 micrograms) produced a marked reduction in the vascular density of the CAM. Thymidine uptake by the CAM was reduced by approximately 65% after exposure to 250 micrograms of FAA. Preliminary findings using a syngeneic rat tumor model suggested that co-injection of tumor cells and FAA can prevent the appearance of palpable subcutaneous tumors.